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BioMed Research International

Volume 2021, Article ID 1940549, 7 pages
https://doi.org/10.1155/2021/1940549

Research Article
Effects of Different Intervention Time Points of Early
Rehabilitation on Patients with Acute Ischemic Stroke: A Single-
Center, Randomized Control Study

LiLi Liu ,1 YanQin Lu ,2 QianQian Bi ,3 Wang Fu ,3 XiaoYu Zhou ,3

and Jue Wang 3
1
Department of Neurology, Shanghai Hongkou District Jiangwan Hospital, The First Rehabilitation Hospital Affiliated to Shanghai
University of Medicine & Health Sciences, 1878 Sichuan North Road, Shanghai 200081, China
2
Department of Infectious, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road,
Shanghai 200072, China
3
Department of Neurology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road,
Shanghai 200072, China

Correspondence should be addressed to XiaoYu Zhou; xiaoyuzhou1979@163.com and Jue Wang; wangjueshiyuan@163.com

Received 12 May 2021; Revised 2 August 2021; Accepted 9 August 2021; Published 29 August 2021

Academic Editor: Qian Wang

Copyright © 2021 LiLi Liu et al. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objective. To investigate effects of different intervention time points of early rehabilitation on patients with acute ischemic stroke.
Methods. We enrolled patients diagnosed with acute ischemic stroke in our hospital’s rehabilitation ward from November 2013 to
December 2015. Patients were randomly assigned to an ultraearly rehabilitation program (started within 72 hours of onset) or an
early rehabilitation program (started from 72 hours to 7 days after onset). The efficacy was assessed by the NIH Stroke Scale
(NIHSS) International, Barthel Index, and Fugl-Meyer Assessment at one and three months after rehabilitation. Data were
analyzed by variance analysis of two-factor repeated measurement. Covariance analysis was used to adjust confounding factors
for the determination of statistical differences. Results. 41 patients were enrolled in the ultraearly rehabilitation group, while 45
patients were in the early rehabilitation group. There were no differences between the two groups at baseline data. Compared
with the early rehabilitation group, patients in the ultraearly rehabilitation group have significantly improved NIHSS score,
BMI score, and FMA score at one month and three months (P < 0:001). After adjusting for confounding factors (gender, age,
severity of NIHSS score, location of stroke, hypertension, diabetes, atrial fibrillation, and coronary heart disease), the significant
difference still existed between the two groups at one month and three months (P < 0:001). Conclusion. Our study indicated a
higher efficacy in the ultraearly rehabilitation group than the early rehabilitation group. The result suggests an important
practical significance in favor of the clinical treatment of stroke.

1. Introduction Early rehabilitation plays a critical role in improving post-

AS the leading cause of disability, stroke imposes a heavy
burden on health care system. Epidemiological data shows
the prevalence of stroke in China is approximately 336.3 in
100,000 people, and disability-adjusted life years (DALYS)
reaches -27.3 to -23.0/100,000 [1]. Therefore, it is imperative
to reduce the disability rate following stroke. The modern
rehabilitation theory considers early rehabilitation interven-
tion is essential for cerebral ischemic stroke patients [2].
stroke disability and helping patients return to society [3].
Studies demonstrated patients with acute ischemic stroke
entered a stable period after 24 to 48 hours of onset [4–6].
Therefore, it laid the theoretical foundation for the safety
of early rehabilitation. Moreover, early rehabilitation
improves the rehabilitation effect and reduced other compli-
cations [7–9]. Emerging evidence suggested early rehabilita-
tion following stroke should be initiated as early as possible
[10, 11]. American Heart Association (AHA)/American
2 BioMed Research International

Enrollment

Patients assessed for eligibility (n = 96)

Patients excluded (n = 6)

Declined to participate (n = 5)

Patients not meeting inclusion criteria (n = 1)

Randomised (n = 90)

Patient allocation

Patients allocated to the ultra-early rehabilitation group (n = 45) Patients allocated to the early rehabilitation group (n = 45)

Patients that received allocated intervention (n = 43) Patients that received allocated intervention (n = 45)

Patients that did not receive allocated intervention (n = 2) Patients that did not receive allocated intervention (n = 0)

Patients that withdrawed consent (n = 2)

Patient follow-up

Patient follow-up (n = 43) Patient follow-up (n = 45)

Time to follow-up: Time to follow-up:

1 month (n = 43) 3 months (n = 41) 1 month (n = 45) 3 months (n = 45)

Lost prior to follow-up (n = 2)

Patients that completed the study and continued allocated Patients that completed the study and continued allocated
intervention (n = 41) intervention (n = 45)

Figure 1: Flowchart of the study population.

Table 1: Basic characteristics of the ultraearly rehabilitation group

Stroke Association (ASA) recommended early rehabilitation and the early rehabilitation group with acute ischemic stroke.
to the patients hospitalized for stroke [12, 13]. Bernhardt
et al. brought forward the concept of early rehabilitation 24 Ultraearly group Early group
Variables P value
hours after the stroke [14]. AVERT trial demonstrated the (n = 41) (n = 45)
efficacy and safety of very early mobilization within 24 hours Gender (m/f) 25/16 29/16 0.740
of stroke onset [15]. An observational study indicated the Age at admission
early rehabilitation, as early as 48-72 hours after stroke 76:5 ± 6:36 71:5 ± 14:8 0.961
(mean ± SD)
onset, was safe and effective in patients with ischemic
Location of stroke
stroke [16].
However, the optimal intervention time point for early The left hemisphere 20 25
rehabilitation is unclear. To date, the definite theory on the The right hemisphere 18 18 0.752
time point of early activities after stroke is not elucidated. Brain stem 3 2
Likewise, the researches in this field are insufficient. A study Severity of NIHSS
by Bernhardt et al. confirmed the effectiveness and safety of score
ultraearly activities in either hemorrhagic stroke or ischemic Light 9 6
stroke patients [14]. The importance of improving activity Moderate 30 38 0.487
levels and effectiveness of interventions to increase physical
Severe 2 1
activity after stroke need to be tested further [17]. A survey
investigated the attitudes of medical practitioners showing
that 77% of experts recognized the early rehabilitation
within 24 hours after the stroke [18–20].
BioMed Research International
Table 2: Comparison of neurological deficits (NIHSS score) between ultraearly rehabilitation group and the early rehabilitation group ðx+sÞ.
Group Cases
At admission
Ultraearly group 41 10:02 ± 5:88
Early group 45 8:40 ± 4:21
Intragroup (repeated interaction) comparison: F = 253:433 (P < 0:001). Intergroup comparison: F = 35:710 (P < 0:001).
Therefore, we launched the study to explore the efficacy
and timing of early rehabilitation in stroke patients.
2. Methods
2.1. Participants. The clinical trial registration number was
ChiCTR1800019305. The Ethics Committee of Shanghai
Jiangwan Hospital approved the study. All participants
recruited from Shanghai City Hospital of Jiangwan
between November 2013 and December 2015 signed writ-
ten informed consent. The inclusion criteria in this study
were as follows: (1) ischemic stroke is confirmed by cra-
nial CT or MRI; (2) patients present with hemiplegia or
hemiparesis with muscle power less than or equal to IV
class; (3) patients’ vital signs and nervous system are sta-
ble; and (4) patients consent to participation in rehabilita-
tion training. The exclusion criteria were as follows: (1)
subarachnoid hemorrhage or intracranial venous thrombo-
sis patients; (2) patients suffering from a severe lung infec-
tion, liver disease, kidney disease, heart disease, or other
essential organ damages; (3) unable to receive rehabilita-
tion training for severe cognitive impairment; (4) unable
to receive rehabilitation training for mental retardation
or conscious disturbance; and (5) patients having neuro-
logical or musculoskeletal disorders affecting functional
recovery.
2.2. Grouping. The patients were randomly divided into the
ultraearly rehabilitation group (started within 72 hours)
and early rehabilitation group (started from 72 hours to 7
days). All patients accepted rehabilitation from professional
physical therapists. Rehabilitation of both groups did not
start until the patients reached stable conditions. Except
for intervention time points, the rehabilitation programs
conducted in both groups were the same. Rehabilitation pro-
grams mainly included Bobath rehabilitation technique,
brain circulation therapy apparatus, and electromyographic
biofeedback technique. Bobath rehabilitation technology
included the following:
(1) Good positioning: families and nursing staff coun-
seled patients using correct posture. Patients were
decubitus lateral or supine lateral and were guided
to turn over every 2 hours. Patients were asked to
avoid abnormal patterns of upper limb flexion, lower
limb extension, and varus foot alignment.
(2) Bed position and joint training activities: hands and
ten fingers cross each other on the ipsilateral hand
grip, with the thumb placed on the top; with the
healthy limb to limb disease, do elbow lift move-
3
NIHSS
Treatment after 1 month Treatment after 3 months
5:02 ± 3:37 3:10 ± 2:26
6:71 ± 3:83 4:98 ± 3:31
ment; upper limb joint activity includes side to lift,
lower limb flexion, and legs and the bed support
hips, namely, the bridge movement.
(3) Balance sitting and sit up training: correct hand,
arm, and leg movements were shown.
(4) Sit up and standing balance training: patients with
lower limb muscle strength of grade 3 and above
were trained to stand. Patients began stand training
using parallel bars, and the standing time gradually
increased.
(5) Walk training: patients that showed an increase in
the weight-bearing strength of their lower limbs
started walk training. Gradually, patients were
trained to step over different obstacles and up and
down stairs.
Brain circulation therapy apparatus and EMG biofeed-
back technique were used to increase cerebral blood supply,
activate brain cells, and improve local muscle spasticity, tic,
and paralysis to improve muscle strength and motor func-
tion. The above rehabilitation exercises were performed 20-
30 min per day, 2-3 times a day, and 4-5 days a week for a
total of three months.
Besides rehabilitation, the other therapies followed the
guidelines of treatment of acute ischemic cerebrovascular
disease. Two weeks after treatment in the ward, the patient
continued rehabilitation treatment in outpatient.
2.3. Clinical Assessments. The U.S. National Institutes of
Health Stroke Scale (NIHSS) assessed the severity of neu-
rological deficit. The modified Barthel Index (MBI) was
introduced to evaluate daily life activity, and the simple
Fugl-Meyer Assessment (FMA) was adopted to determine
motor function. Neurologists and rehabilitation physicians
in this study accepted specific training in NIHSS, MBI,
and FMA assessments. We collected characteristics of
patients, including gender, age, NIHSS score, location of
the lesion, history of hypertension, history of diabetes, his-
tory of coronary heart disease, and history of atrial fibril-
lation. According to NIHSS 0-5, NIHSS 6-20, or NIHSS
greater than 20, respectively, all patients were defined as
mild, moderate, or severe neurologic deficit. The locations
of the lesions included the right hemisphere, left hemi-
sphere, and brain stem. All data were recorded in a unified
form.
2.4. Randomization, Masking, and Procedures. All eligible
patients with acute ischemic stroke were randomized to
receive either ultraearly rehabilitation or early rehabilitation
4 BioMed Research International

Table 3: Comparison of Barthel Index (MBI) between the ultraearly rehabilitation group and the early rehabilitation group ðx+sÞ.

MBI
Group Cases
At admission Treatment after 1 month Treatment after 3 months
Ultraearly group 41 47:32 ± 10:07 62:31 ± 10:37 73:90 ± 12:48
Early group 45 48:10 ± 9:90 55:78 ± 8:05 62:24 ± 8:77
Intragroup (repeated interaction) comparison: F = 758:093 (P < 0:001). Intergroup comparison: F = 86:333 (P < 0:001).

Table 4: Comparison of motor function (FMA) between the ultraearly rehabilitation group and the early rehabilitation group ðx+sÞ.

FMA
Group Cases
At admission Treatment after 1 month Treatment after 3 months
Ultraearly group 41 47:73 ± 11:08 62:80 ± 11:26 78:12 ± 13:19
Early group 45 50:69 ± 7:34 57:98 ± 7:46 63:91 ± 8:74
Intragroup (repeated interaction) comparison: F = 842:880 (P < 0:001). Intergroup comparison: F = 130:962 (P < 0:001).

Table 5: ANCOVA of the factors that affected change of NIHSS score in one month and three months following rehabilitation.

ΔNIHSS Factors DF MS F value P value

Group 1 265.670 85.199 .000
Gender 1 15.029 4.820 .031
Age 1 1.504 .482 .489
Severity of NIHSS score 1 117.400 37.650 .000
1 month Location of stroke 1 .062 .020 .888
Hypertension 1 .329 .105 .746
Diabetes 1 2.498 .801 .374
Coronary heart disease 1 5.973 1.915 .170
Atrial fibrillation 1 .744 .239 .627
Group 1 307.883 58.531 .000
Gender 1 28.635 5.444 .022
Age 1 3.033 .577 .450
Severity of NIHSS score 1 263.925 50.174 .000
3 months Location of stroke 1 2.371 .451 .504
Hypertension 1 .037 .007 .934
Diabetes 1 10.733 2.040 .157
Coronary heart disease 1 8.396 1.596 .210
Atrial fibrillation 1 .016 .003 .956
ΔNIHSS: change of NIHSS score; DF: degree of freedom; MS: mean square. Significance: P < 0:05.

with the ratio of 1 : 1. NIHSS, BMI, and FMA were assessed
at baseline, one month, and three months by the evaluators
who were blind to the outcome of randomization.
2.5. Statistical Analysis. SPSS19.0 statistical analysis software
was used for analysis. The differences in baseline demo-
graphic and clinical characteristics were analyzed by a chi-
square test and t-test. The analyses of repeated measurement
data used variance analysis of two-factor repeated measure-
ment. Covariance analysis was used to adjust the confound-
ing factors and determine the statistical significance of
dependent variables. P < 0:05 was accepted as indicative of
significant differences.
3. Results
90 out of 96 eligible participants were recruited and assigned
randomly to one of two groups. Among the 96 participants,
88 completed the 1-month trial, and 86 patients completed
the 3-month trial. There were two patient dropouts in the
ultraearly rehabilitation group at the beginning of rehabilita-
tion. Two cases were lost at follow-up in the ultraearly reha-
bilitation group at three months (Figure 1).
At baseline, there were no significant differences in the
severity of disability, age, gender, locations of lesions, and
medicine between the two groups (Table 1). Neurologic
function, daily living activities, and motor function
BioMed Research International 5

Table 6: ANCOVA of the factors that affected change of MBI score in one month and three months following rehabilitation.

Δ MBI Factors DF MS F value P value

Group 1 1092.659 27.541 .000
Gender 1 2.455 .062 .804
Age 1 1.144 .029 .866
Severity of NIHSS score 1 3.908 .099 .754
1 month Location of stroke 1 20.868 .526 .471
Hypertension 1 4.387 .111 .740
Diabetes 1 43.801 1.104 .297
Coronary heart disease 1 13.906 .351 .556
Atrial fibrillation 1 17.214 .434 .512
Group 1 3184.419 59.851 .000
Gender 1 .094 .002 .967
Age 1 1.135 .021 .884
Severity of NIHSS score 1 52.374 .984 .324
3 months Location of stroke 1 2.293 .043 .836
Hypertension 1 28.252 .531 .468
Diabetes 1 41.375 .778 .381
Coronary heart disease 1 96.928 1.822 .181
Atrial fibrillation 1 5.585 .105 .747
ΔMBI: change of NIHSS score; DF: degree of freedom; MS: mean square. Significance: P < 0:05.

Table 7: ANCOVA of the factors that affected change of FMA score in one month and three months following rehabilitation.

ΔFMA Factors DF MS F value P value

Group 1 1252.803 103.570 .000
Gender 1 .119 .010 .921
Age 1 16.233 1.342 .250
Severity of NIHSS score 1 7.172 .593 .444
1 month Location of stroke 1 11.948 .988 .323
Hypertension 1 3.915 .324 .571
Diabetes 1 14.156 1.170 .283
Coronary heart disease 1 18.662 1.543 .218
Atrial fibrillation 1 .654 .054 .817
Group 1 6182.668 209.557 .000
Gender 1 10.327 .350 .556
Age 1 15.514 .526 .471
Severity of NIHSS score 1 14.890 .505 .480
3 months Location of stroke 1 2.609 .088 .767
Hypertension 1 19.168 .650 .423
Diabetes 1 44.121 1.495 .225
Coronary heart disease 1 23.142 .784 .379
Atrial fibrillation 1 2.306 .078 .781
ΔNIHSS: change of FMA score; DF: degree of freedom; MS: mean square. Significance: P < 0:05.

improved after rehabilitation in both groups. As shown in
Tables 2–4, NIHSS scores were lower in the ultraearly reha-
bilitation group than in the early rehabilitation group at one
month and three months [intragroup (repeated interaction)
comparison: F = 253:433 (P < 0:001)], while MBI scores and
FMA were higher in the ultraearly rehabilitation group than
in the early rehabilitation group [intragroup (repeated inter-
action) comparison for MBI: F = 758:093 (P < 0:001);
intragroup (repeated interaction) comparison for FMA: F
= 842:880 (P < 0:001)]. Covariance analysis showed the dif-
ferences remained statistically significant after adjusting for
confusing factors at 1-month and 3-month (Tables 5–7).
6 BioMed Research International
Moreover, gender and the severity of neurology deficit at
onset were independently correlated to NIHSS, MBI, and
FMA at one month and three months.
4. Discussion
Our results indicated the efficacy of ultraearly patient reha-
bilitation within 72 hours outmatched that of early restora-
tion. Previous studies supported our conclusions [2]. It is
consistent with Bernhardt, et al.’s study which showed the
validity and safety of ultraearly events, and results confirmed
the effectiveness and safety of ultraearly events [14].
The theory of neural plasticity and functional reorgani-
zation accounts for our result [21–23]. In these two theoret-
ical studies, early rehabilitation training facilitates
neuroplasticity and functional reorganization. Moreover,
changes in the brain tissue structure provide the foundation
for neuroplasticity and functional recovery after stroke. In
animal models, ischemia induces sprouting of new dendrites
and axons, primarily in the perilesional cortex and in regions
of molecular plasticity remote from the lesion [24]. Growth
factor signals promoting synaptogenesis can be detected as
early as three days poststroke and reaches the highest
between 7 and 14 days [25, 26]. Compared with the recovery
stage, acute stroke leads to distinct remote inhibitory effects,
inflammatory reactions and inflammatory factors (such as
hs-CRP, IL-1, and IL-6). With brain cell damaging, remote
inhibitory effects may be independently associated with
immediate neurological deficits. In the acute phase of stroke,
the inflammatory response on brain cells is neurotoxic,
which blocks nerve remodeling and inhibits nerve conduc-
tion. Therefore, inhibition of neuron recovery is more in
the acute phase than in the recovery phase. Ultraearly inter-
vention treatment reduces remote inhibitory effects and
inflammatory response, thereby accelerating the rehabilita-
tion and improving the rehabilitation effect.
In addition, early rehabilitation improves the early sur-
vival of brain cells by increasing cerebral blood flow (CBF)
and reducing the penumbra around the lesion. Increasing
CBF contributes to reducing ischemic necrosis of neurons
in the penumbra zone. Sensory impulse is repeatedly intro-
duced into the central nervous system, which plays an essen-
tial role in axon sprouting of neurons, transmission of latent
pathways, and synapses. Therefore, ultraearly rehabilitation
increases the CBF in the penumbra area and revitalizes a
part of the neuron [27]. A study using a rat model of cerebral
infarction indicated physical activities within 14 days of
onset reduced dendritic branching and prevented the aggra-
vation of nerve conduction [24]. Early rehabilitation inter-
vention promotes dendritic sprouting, stimulates synaptic
transmission, and increases CBF. Schallert et al. [28] pro-
posed that early stroke rehabilitation intervention results in
better recovery of neurological function after stroke. Natural
recovery leads to further residual dysfunction, misuse gives
rise to residual limb function, and subsequential deteriora-
tion of nerve function contributes to wasting. Therefore,
earlier rehabilitation training prevents injured brain cells,
misuse, and wasting of limbs and promotes the reconstruc-
tion of normal motion mode.
The limitations of our study were that it is a single-center
study and the sample was relatively small. Therefore, the
introduction of bias was possible. However, strict random-
ized design in our study partly reduced the possibility of
bias.
5. Conclusion
Our study showed the efficacy of ultraearly rehabilitation in
neurological function, activities of daily living, and motor
function in patients with acute ischemic stroke. Further large
sample trial is clearly warranted.
Data Availability
The data are available from the corresponding author on
reasonable request.
Ethical Approval
The Ethics Committee of Shanghai Jiangwan Hospital
approved the present project. The project is registered
through clinical trials, and the registration number is
ChiCTR1800019305.
Conflicts of Interest
The authors declare no potential conflicts of interest with
respect to the financial, consultant, institutional and author-
ship, and/or publication of this article.
Authors’ Contributions
LiLi Liu and YanQin Lu contributed equally to this work.
Acknowledgments
Our work was supported by the Excellent Youth Backbone
Project of Hongkou District Wei Planning Commission in
Shanghai (2014-2016). Our work has also been supported
by Shanghai Science and Technology Commission
(19401972804). We thank the rehabilitation and nursing
team who helped with patient treatment at Shanghai
Hongkou District Jiangwan Hospital. We thank the patients
and their families for their participation.
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